There is growing interest in the use of intranasal oxytocin (OT) as a potential treatment for a variety of psychiatric disorders, including autism spectrum disorders (ASD), and preliminary studies show that intranasal OT can indeed alleviate some social cognitive deficits found in ASD individuals. Ultimately, the effectiveness of intranasal OT in treating ASD and other mental disorders will depend upon both the levels of OT it establishes in the brain, as well as the density and distribution of brain OT receptors. DNA methylation of the OXTR gene helps to regulate its expression and may therefore modulate the neural and behavioral responsiveness to intranasal OT treatment as well as its potential clinical effectiveness. This project has two specific aims. Aim 1 is to determine if DNA methylation of OXTR influences cooperative behavior and associated brain activity in humans subjects immersed in genuine social interactions. Methylation status of OXTR will be assessed in our existing sample of 300 subjects from whom we have collected behavioral and fMRI data as they play a social, interactive game with human and computer partners. We hypothesize that methylation will associate with measures of cooperative behavior, as well as to fMRI responses to cooperative and non- cooperative social interactions. Aim 2 will determine if DNA methylation of OXTR modulates the effect of intranasal OT on cooperative behavior and associated brain activity in humans subjects immersed in genuine social interactions. 100 subjects were pre-treated with intranasal OT prior to receiving an fMRI scan while playing a social, interactive game. Another 100 subjects were pre-treated with an intranasal placebo. We hypothesize that methylation levels will be related to the effect of intranasal OT (relative to placebo) on measures of cooperative behavior, as well as to the effects of intranasal OT on fMRI responses to cooperative and non-cooperative social interactions. Ultimately, this research may help us to identify individuals who are most likely to benefit from a treatment like intranasal OT.